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1.
Front Immunol ; 13: 868915, 2022.
Article in English | MEDLINE | ID: covidwho-1793012

ABSTRACT

Background: Immunomodulatory/immunosuppressive activity of multiple sclerosis (MS) disease modifying therapies (DMTs) might affect immune responses to SARS-CoV-2 exposure or vaccination in patients with MS (PwMS). We evaluated the effect of DMTs on humoral and cell-mediated immune responses to 2 and 3 vaccinations and the longevity of SARS-Cov-2 IgG levels in PwMS. Methods: 522 PwMS and 68 healthy controls vaccinated with BNT162b2-Pfizer mRNA vaccine against SARS-CoV-2, or recovering from COVID-19, were recruited in a nation-wide multi-center study. Blood was collected at 3 time-points: 2-16 weeks and ~6 months post 2nd vaccination and 1-16 weeks following 3rd vaccination. Serological responses were measured by quantifying IgG levels against the spike-receptor-binding-domain of SARS-CoV-2, and cellular responses (in a subgroup analysis) by quantifying IFNγ secretion in blood incubated with COVID-19 spike-antigen. Results: 75% PwMS were seropositive post 2nd or 3rd vaccination. IgG levels decreased by 82% within 6 months from vaccination (p<0.0001), but were boosted 10.3 fold by the 3rd vaccination (p<0.0001), and 1.8 fold compared to ≤3m post 2nd vaccination (p=0.025). Patients treated with most DMTs were seropositive post 2nd and 3rd vaccinations, however only 38% and 44% of ocrelizumab-treated patients and 54% and 46% of fingolimod-treated patients, respectively, were seropositive. Similarly, in COVID-19-recovered patients only 54% of ocrelizumab-treated, 75% of fingolimod-treated and 67% of cladribine-treated patients were seropositive. A time interval of ≥5 months between ocrelizumab infusion and vaccination was associated with higher IgG levels (p=0.039 post-2nd vaccination; p=0.036 post-3rd vaccination), and with higher proportions of seropositive patients. Most fingolimod- and ocrelizumab-treated patients responded similarly to 2nd and 3rd vaccination. IFNγ-T-cell responses were detected in 89% and 63% of PwMS post 2nd and 3rd vaccination, however in only 25% and 0% of fingolimod-treated patients, while in 100% and 86% of ocrelizumab-treated patients, respectively. Conclusion: PwMS treated with most DMTs developed humoral and T-cell responses following 2 and 3 mRNA SARS-CoV-2 vaccinations. Fingolimod- or ocrelizumab-treated patients had diminished humoral responses, and fingolimod compromised the cellular responses, with no improvement after a 3rd booster. Vaccination following >5 months since ocrelizumab infusion was associated with better sero-positivity. These findings may contribute to the development of treatment-stratified vaccination guidelines for PwMS.


Subject(s)
COVID-19 , Multiple Sclerosis , COVID-19/prevention & control , COVID-19 Vaccines , Fingolimod Hydrochloride/therapeutic use , Humans , Immunity, Cellular , Immunoglobulin G/therapeutic use , Israel , Multiple Sclerosis/drug therapy , RNA, Messenger/therapeutic use , SARS-CoV-2 , Vaccination , Vaccines, Synthetic
2.
BMJ Case Rep ; 15(3)2022 Mar 15.
Article in English | MEDLINE | ID: covidwho-1745762

ABSTRACT

Systemic capillary leak syndrome (SCLS), also known as Clarkson's disease, is a rare disorder of unknown aetiology. Since SCLS was first described in 1960, fewer than 500 cases have been reported. SCLS is diagnosed by the classic triad of hypotension, haemoconcentration and hypoalbuminaemia resulting from fluid extravasation. Some reports show that SCLS may sometimes occur as a side effect of adenoviral vector COVID-19 vaccines, although there is only one report (two cases) of SCLS after receiving a messenger RNA vaccine. Survival rates for SCLS are very poor without treatment, so it is crucial for clinicians to recognise this disorder. A middle-aged woman who presented with generalised malaise and anasarca after receiving the BNT162b2 COVID-19 vaccine was diagnosed with SCLS. Treatment with methylprednisolone and intravenous immunoglobulin was commenced and her symptoms resolved. We expect that this case report will add to the existing literature on this rare disorder and the side effects of vaccinations.


Subject(s)
COVID-19 , Capillary Leak Syndrome , Vaccines , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Capillary Leak Syndrome/drug therapy , Female , Humans , Middle Aged , RNA, Messenger/therapeutic use , Vaccines/therapeutic use , Vaccines, Synthetic
3.
Biomed Pharmacother ; 145: 112385, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1565522

ABSTRACT

Chemically modified mRNA represents a unique, efficient, and straightforward approach to produce a class of biopharmaceutical agents. It has been already approved as a vaccination-based method for targeting SARS-CoV-2 virus. The COVID-19 pandemic has highlighted the prospect of synthetic modified mRNA to efficiently and safely combat various diseases. Recently, various optimization advances have been adopted to overcome the limitations associated with conventional gene therapeutics leading to wide-ranging applications in different disease conditions. This review sheds light on emerging directions of chemically modified mRNAs to prevent and treat widespread chronic diseases, including metabolic disorders, cancer vaccination and immunotherapy, musculoskeletal disorders, respiratory conditions, cardiovascular diseases, and liver diseases.


Subject(s)
COVID-19/prevention & control , Chronic Disease/prevention & control , Chronic Disease/therapy , Genetic Therapy/methods , Immunotherapy/methods , Pandemics/prevention & control , RNA, Messenger/chemistry , SARS-CoV-2/immunology , Vaccines, Synthetic , Biological Availability , Drug Carriers , Forecasting , Gene Transfer Techniques , Genetic Vectors/administration & dosage , Genetic Vectors/therapeutic use , Humans , Immunotherapy, Active , RNA Stability , RNA, Messenger/administration & dosage , RNA, Messenger/immunology , RNA, Messenger/therapeutic use , SARS-CoV-2/genetics , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/immunology , /immunology
5.
Acc Chem Res ; 54(23): 4283-4293, 2021 12 07.
Article in English | MEDLINE | ID: covidwho-1521679

ABSTRACT

After decades of extensive fundamental studies and clinical trials, lipid nanoparticles (LNPs) have demonstrated effective mRNA delivery such as the Moderna and Pfizer-BioNTech vaccines fighting against COVID-19. Moreover, researchers and clinicians have been investigating mRNA therapeutics for a variety of therapeutic indications including protein replacement therapy, genome editing, and cancer immunotherapy. To realize these therapeutics in the clinic, there are many formidable challenges. First, novel delivery systems such as LNPs with high delivery efficiency and low toxicity need to be developed for different cell types. Second, mRNA molecules need to be engineered for improved pharmaceutical properties. Lastly, the LNP-mRNA nanoparticle formulations need to match their therapeutic applications.In this Account, we summarize our recent advances in the design and development of various classes of lipids and lipid derivatives, which can be formulated with multiple types of mRNA molecules to treat diverse diseases. For example, we conceived a series of ionizable lipid-like molecules based on the structures of a benzene core, an amide linker, and hydrophobic tails. We identified N1,N3,N5-tris(3-(didodecylamino)propyl)benzene-1,3,5-tricarboxamide (TT3) as a lead compound for mRNA delivery both in vitro and in vivo. Moreover, we tuned the biodegradability of these lipid-like molecules by introducing branched ester or linear ester chains. Meanwhile, inspired by biomimetic compounds, we synthesized vitamin-derived lipids, chemotherapeutic conjugated lipids, phospholipids, and glycolipids. These scaffolds greatly broaden the chemical space of ionizable lipids for mRNA delivery. In another section, we highlight our efforts on the research direction of mRNA engineering. We previously optimized mRNA chemistry using chemically-modified nucleotides to increase the protein expression, such as pseudouridine (ψ), 5-methoxyuridine (5moU), and N1-methylpseudouridine (me1ψ). Also, we engineered the sequences of mRNA 5' untranslated regions (5'-UTRs) and 3' untranslated regions (3'-UTRs), which dramatically enhanced protein expression. With the progress of LNP development and mRNA engineering, we consolidate these technologies and apply them to treat diseases such as genetic disorders, infectious diseases, and cancers. For instance, TT3 and its analog-derived lipid-like nanoparticles can effectively deliver factor IX or VIII mRNA and recover the clotting activity in hemophilia mouse models. Engineered mRNAs encoding SARS-CoV-2 antigens serve well as vaccine candidates against COVID-19. Vitamin-derived lipid nanoparticles loaded with antimicrobial peptide-cathepsin B mRNA enable adoptive macrophage transfer to treat multidrug resistant bacterial sepsis. Biomimetic lipids such as phospholipids formulated with mRNAs encoding costimulatory receptors lead to enhanced cancer immunotherapy.Overall, lipid-mRNA nanoparticle formulations have considerably benefited public health in the COVID-19 pandemic. To expand their applications in clinical use, research work from many disciplines such as chemistry, engineering, materials, pharmaceutical sciences, and medicine need to be integrated. With these collaborative efforts, we believe that more and more lipid-mRNA nanoparticle formulations will enter the clinic in the near future and benefit human health.


Subject(s)
Drug Carriers/chemistry , Liposomes/chemistry , Nanoparticles/chemistry , RNA, Messenger/chemistry , Animals , Benzamides/chemistry , Biomimetic Materials/chemistry , Communicable Diseases/immunology , Communicable Diseases/therapy , Disease Models, Animal , Genetic Diseases, Inborn/immunology , Genetic Diseases, Inborn/therapy , Humans , Mice , Neoplasms/immunology , Neoplasms/therapy , Phospholipids/chemistry , RNA, Messenger/metabolism , RNA, Messenger/therapeutic use , Untranslated Regions , Vitamins/chemistry
6.
Adv Drug Deliv Rev ; 179: 114002, 2021 12.
Article in English | MEDLINE | ID: covidwho-1465981

ABSTRACT

After thirty years of intensive research shaping and optimizing the technology, the approval of the first mRNA-based formulation by the EMA and FDA in order to stop the COVID-19 pandemic was a breakthrough in mRNA research. The astonishing success of these vaccines have brought the mRNA platform into the spotlight of the scientific community. The remarkable persistence of the groundwork is mainly attributed to the exceptional benefits of mRNA application, including the biological origin, immediate but transitory mechanism of action, non-integrative properties, safe and relatively simple manufacturing as well as the flexibility to produce any desired protein. Based on these advantages, a practical implementation of in vitro transcribed mRNA has been considered in most areas of medicine. In this review, we discuss the key preconditions for the rise of the mRNA in the medical field, including the unique structural and functional features of the mRNA molecule and its vehicles, which are crucial aspects for a production of potent mRNA-based therapeutics. Further, we focus on the utility of mRNA tools particularly in the scope of regenerative medicine, i.e. cell reprogramming approaches or manipulation strategies for targeted tissue restoration. Finally, we highlight the strong clinical potential but also the remaining hurdles to overcome for the mRNA-based regenerative therapy, which is only a few steps away from becoming a reality.


Subject(s)
Cell- and Tissue-Based Therapy/methods , RNA, Messenger/therapeutic use , Regenerative Medicine/trends , Tissue Engineering/methods , Animals , COVID-19 , Humans
8.
J Am Chem Soc ; 143(14): 5413-5424, 2021 04 14.
Article in English | MEDLINE | ID: covidwho-1387160

ABSTRACT

Methods for tracking RNA inside living cells without perturbing their natural interactions and functions are critical within biology and, in particular, to facilitate studies of therapeutic RNA delivery. We present a stealth labeling approach that can efficiently, and with high fidelity, generate RNA transcripts, through enzymatic incorporation of the triphosphate of tCO, a fluorescent tricyclic cytosine analogue. We demonstrate this by incorporation of tCO in up to 100% of the natural cytosine positions of a 1.2 kb mRNA encoding for the histone H2B fused to GFP (H2B:GFP). Spectroscopic characterization of this mRNA shows that the incorporation rate of tCO is similar to cytosine, which allows for efficient labeling and controlled tuning of labeling ratios for different applications. Using live cell confocal microscopy and flow cytometry, we show that the tCO-labeled mRNA is efficiently translated into H2B:GFP inside human cells. Hence, we not only develop the use of fluorescent base analogue labeling of nucleic acids in live-cell microscopy but also, importantly, show that the resulting transcript is translated into the correct protein. Moreover, the spectral properties of our transcripts and their translation product allow for their straightforward, simultaneous visualization in live cells. Finally, we find that chemically transfected tCO-labeled RNA, unlike a state-of-the-art fluorescently labeled RNA, gives rise to expression of a similar amount of protein as its natural counterpart, hence representing a methodology for studying natural, unperturbed processing of mRNA used in RNA therapeutics and in vaccines, like the ones developed against SARS-CoV-2.


Subject(s)
Fluorescence , Fluorescent Dyes/analysis , Fluorescent Dyes/chemistry , Molecular Imaging , RNA, Messenger/analysis , RNA, Messenger/metabolism , COVID-19/drug therapy , Cell Line, Tumor , Cytosine/analogs & derivatives , Cytosine/analysis , Cytosine/chemical synthesis , Cytosine/chemistry , Fluorescent Dyes/chemical synthesis , Green Fluorescent Proteins/metabolism , Histones/metabolism , Humans , Molecular Structure , RNA, Messenger/chemistry , RNA, Messenger/therapeutic use , Spectrometry, Fluorescence
10.
Drug Discov Ther ; 15(4): 222-224, 2021 Sep 22.
Article in English | MEDLINE | ID: covidwho-1317319

ABSTRACT

In December 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the outbreak of coronavirus disease 2019 (COVID-19), and the resulting pandemic has caused widespread health problems and social and economic disruption. Thus far in 2021, more than 4 million people worldwide have died from COVID-19, so safe and efficacious vaccines are urgently needed to restore normal economic and social activities. According to the official guidance documents of the World Health Organization (WHO), vaccines based on four major strategies including mRNA, adenoviral vectors, inactivated viruses, and recombinant proteins have entered the stage of emergency use authorization and pre-certification evaluation. The current review summarizes these vaccines and it looks ahead to the development of additional COVID-19 vaccines in the future.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Drug Approval/organization & administration , COVID-19 Vaccines/classification , Humans , RNA, Messenger/therapeutic use , RNA, Viral/therapeutic use , Vaccines, Inactivated/therapeutic use , World Health Organization
12.
J Allergy Clin Immunol ; 147(6): 2075-2082.e2, 2021 06.
Article in English | MEDLINE | ID: covidwho-1185028

ABSTRACT

Anaphylaxis to vaccines is historically a rare event. The coronavirus disease 2019 pandemic drove the need for rapid vaccine production applying a novel antigen delivery system: messenger RNA vaccines packaged in lipid nanoparticles. Unexpectedly, public vaccine administration led to a small number of severe allergic reactions, with resultant substantial public concern, especially within atopic individuals. We reviewed the constituents of the messenger RNA lipid nanoparticle vaccine and considered several contributors to these reactions: (1) contact system activation by nucleic acid, (2) complement recognition of the vaccine-activating allergic effector cells, (3) preexisting antibody recognition of polyethylene glycol, a lipid nanoparticle surface hydrophilic polymer, and (4) direct mast cell activation, coupled with potential genetic or environmental predispositions to hypersensitivity. Unfortunately, measurement of anti-polyethylene glycol antibodies in vitro is not clinically available, and the predictive value of skin testing to polyethylene glycol components as a coronavirus disease 2019 messenger RNA vaccine-specific anaphylaxis marker is unknown. Even less is known regarding the applicability of vaccine use for testing (in vitro/vivo) to ascertain pathogenesis or predict reactivity risk. Expedient and thorough research-based evaluation of patients who have suffered anaphylactic vaccine reactions and prospective clinical trials in putative at-risk individuals are needed to address these concerns during a public health crisis.


Subject(s)
Anaphylaxis/immunology , COVID-19 Vaccines/adverse effects , COVID-19/immunology , Drug Hypersensitivity/immunology , Lipids/adverse effects , Nanoparticles/adverse effects , RNA, Messenger/adverse effects , SARS-CoV-2/immunology , Anaphylaxis/chemically induced , Animals , COVID-19/prevention & control , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Drug Hypersensitivity/pathology , Humans , Lipids/immunology , Lipids/therapeutic use , Mast Cells/immunology , Mast Cells/pathology , Nanoparticles/therapeutic use , RNA, Messenger/immunology , RNA, Messenger/therapeutic use , Risk Factors
13.
J Am Chem Soc ; 143(14): 5413-5424, 2021 04 14.
Article in English | MEDLINE | ID: covidwho-1164792

ABSTRACT

Methods for tracking RNA inside living cells without perturbing their natural interactions and functions are critical within biology and, in particular, to facilitate studies of therapeutic RNA delivery. We present a stealth labeling approach that can efficiently, and with high fidelity, generate RNA transcripts, through enzymatic incorporation of the triphosphate of tCO, a fluorescent tricyclic cytosine analogue. We demonstrate this by incorporation of tCO in up to 100% of the natural cytosine positions of a 1.2 kb mRNA encoding for the histone H2B fused to GFP (H2B:GFP). Spectroscopic characterization of this mRNA shows that the incorporation rate of tCO is similar to cytosine, which allows for efficient labeling and controlled tuning of labeling ratios for different applications. Using live cell confocal microscopy and flow cytometry, we show that the tCO-labeled mRNA is efficiently translated into H2B:GFP inside human cells. Hence, we not only develop the use of fluorescent base analogue labeling of nucleic acids in live-cell microscopy but also, importantly, show that the resulting transcript is translated into the correct protein. Moreover, the spectral properties of our transcripts and their translation product allow for their straightforward, simultaneous visualization in live cells. Finally, we find that chemically transfected tCO-labeled RNA, unlike a state-of-the-art fluorescently labeled RNA, gives rise to expression of a similar amount of protein as its natural counterpart, hence representing a methodology for studying natural, unperturbed processing of mRNA used in RNA therapeutics and in vaccines, like the ones developed against SARS-CoV-2.


Subject(s)
Fluorescence , Fluorescent Dyes/analysis , Fluorescent Dyes/chemistry , Molecular Imaging , RNA, Messenger/analysis , RNA, Messenger/metabolism , COVID-19/drug therapy , Cell Line, Tumor , Cytosine/analogs & derivatives , Cytosine/analysis , Cytosine/chemical synthesis , Cytosine/chemistry , Fluorescent Dyes/chemical synthesis , Green Fluorescent Proteins/metabolism , Histones/metabolism , Humans , Molecular Structure , RNA, Messenger/chemistry , RNA, Messenger/therapeutic use , Spectrometry, Fluorescence
16.
Cells ; 10(1)2021 Jan 19.
Article in English | MEDLINE | ID: covidwho-1041449

ABSTRACT

mRNA has emerged as an important biomolecule in the global call for the development of therapies during the COVID-19 pandemic. Synthetic in vitro-transcribed (IVT) mRNA can be engineered to mimic naturally occurring mRNA and can be used as a tool to target "undruggable" diseases. Recent advancement in the field of RNA therapeutics have addressed the challenges inherent to this drug molecule and this approach is now being applied to several therapeutic modalities, from cancer immunotherapy to vaccine development. In this review, we discussed the use of mRNA for stem cell generation or enhancement for the purpose of cardiovascular regeneration.


Subject(s)
Cardiovascular Diseases/therapy , Cell- and Tissue-Based Therapy , RNA, Messenger/therapeutic use , Regeneration , Humans , Stem Cells
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